Neel Gandhi, M.D., is a physician-scientist at Emory's Rollins School of Public Health with 80% effort dedicated to patient-oriented research (POR). He seeks funding through the K24 Midcareer Investigator Award to expand his POR program in drug-resistant tuberculosis (TB), HIV and global health, and to mentor clinical investigators in these areas. The intersection between drug-resistant TB and HIV is an emerging global public health issue which threatens a decade of gains in TB control. There is a growing need for innovative research in TB genomics, immunology, and therapeutics, in addition to developing a pool of scientists trained in TB/HIV and global health POR. Dr. Gandhi has demonstrated a commitment to clinical, epidemiologic and translational research in TB/HIV and global health over the past decade, including a strong record of successfully mentoring 24 trainees, to date. Emory University provides a robust environment for training clinical investigators through its degree programs (MPH, MS, PhD), post-doctoral fellowships and multi-disciplinary centers (CTSA, CFAR, Global Health). Within this highly conducive training environment, Dr. Gandhi has created a comprehensive mentoring program that focuses on the design and responsible conduct of hypothesis-driven research to assist trainees in becoming independent investigators. This K24 award will greatly facilitate the PI's immediate and long-term career goals, which include to: 1) Understand how whole genome sequencing can further elucidate mechanisms of acquired resistance and transmission in drug- resistant TB epidemics; 2) Advance his knowledge of human immunology to inform future studies of increased TB susceptibility among HIV-infected individuals; 3) Expand clinical trials skills to facilitate the design and implementation of drug-resistant TB and TB/HIV trials; and 4) Enhance the structure and content of his mentorship of trainees pursuing careers in patient- oriented TB, HIV and Global Health research. This award will utilize a framework of multiple NIH-funded studies in drug-resistant TB and HIV in South Africa to investigate two novel specific research aims: 1) To examine polymorphisms in the M.tuberculosis genome which arise among MDR TB subjects who develop additional resistance on treatment, and 2) To investigate the incremental yield of whole genome sequencing in identifying micro-clusters of XDR TB transmission in large genotypic clusters. The K24 award will allow Dr. Gandhi to continue his highly-successful research program in TB, HIV and global health, and mentor the next generation of investigators in this vital research field.